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1 Cancer Vaccines Eun-Wha Son 1, Sang-Whan In 2 and Suhkneung Pyo 2 1 Department of Pharmacognosy Material Development, Samcheok National University, Samcheok, 2 Division of Immunopharmacology, College of Pharmacy, Sungkyunkwan University, Suwon, Korea ABSTRACT Cancer vaccine is an active immunotherapy to stimulate the immune system to mount a response against the tumor specific antigen. Working as a stimulant to the body s own immune system, cancer vaccines help the body recognize and destroy targeted cancers and may help to shrink advanced tumors. Research is currently underway to develop therapeutic cancer vaccines. It is also possible to develop prophylactic vaccines in the future. The whole cell approach to eradicate cancer has used whole cancer cells to make vaccine. In an early stage of this approach, whole cell lysate or a mixture of immunoadjuvant and inactivated cancer cells has been used. Improved vaccines are being developed that utilize cytokines or costimulatory molecules to mount an attack against cancer cells. In case of melanoma, these vaccines are expected to have a therapeutic effect of vaccine. Furthermore, it is attempting to treat stomach cancer, colorectal cancer, pancreatic cancer, and prostate cancer. Other vaccines are being developing that are peptide vaccine, recombinant vaccine and dendritic cell vaccine. Out of them, reintroduction of antigen-specific dendritic cells into patient and DNA vaccine are mostly being conducted. Currently, research and development efforts are underway to develop therapeutic cancer vaccine such as DNA vaccine for the treatment of multiple forms of cancers. (Immune Network 2005;5(2):55-67) Key Words: Cancer vaccine, DNA, dendritic cell, immunotherapy Immune Network 55

2 56 Eun-Wha Son, et al. Tumor-infiltrating macrophage IL-10 Mature DC HLA I & II B7.1 B7.2 Naive HTL CD28 CTLA-4 Naïve CTL Effector HTL Th1 TCR CD4 CD40-L IL-13 TGFβ IL-10 TCR CD4 CD25 NKT cell Tr cell ROS CD40 CD11b Gr-1 Myeloid suppressor cell NK cell TAA HSP dsdna Perforin Granzyme FAS-L FAS Perforin Granzyme FAS-L TCR CD8 Effector CTL B7-H1 Tolerogenic DC FAS-L PGE2 TGFβ NO Class I HLA & TAA-derived peptide Tumor cells Figure 1. The immune response to tumor cells (full lines: stimulatory effect, dotted lines: inhibitory effect).

3 Cancer Vaccines 57 Table I. Approach of cancer vaccine Vaccine Components Contents Polyvalent vaccines Whole tumor cell Auogous or allogeneic tumor cells that can be genetically engineered to secrete cytokines No need to know the molecular identity of TAA Lysate tumor cell Mechanical, enzymatic, or viral tumor lysates No need to know the molecular identity of TAA Shared antigens TAA or TAA-derived peptides released in vitro by allogeneic tumor cell lines No need to know the molecular identity of TAA Heat shock proteins Prepared from auogous tumor cells No need to know the molecular identity of TAA Antigen-defined vaccines TAA Proteins (eg., CEA, p53), idiotypes (lymphoma, multiple myeloma), glycoproteins (eg., MUC-1), glycolipids (eg., gangliosides) Peptides HLA class I or class II restricted Recombirart DNA Genetically engineered to express TAA±cytokines Recombinart vins Genetically engineered to express TAA±cytokines Anti-idiotypic antibody Mimicking the natural TAA Dendritic cell-based vaccines Tumor-DC hybrids No need to know the molecular identity of TAA Peptide loaded DC HLA class I or class II restricted Whole tumor cell loaded DC Auogous or allogeneic tumor cells No need to know the molecular identity of TAA Tumor mrna loaded DC No need to know the molecular identity of TAA Genetically engineered DC Engineered to secrete cytokines or express TAA TAA: tumor associated antigens, DC: dendritie cell.

4 58 Eun-Wha Son, et al. Table II. Tumor-associated antigens Scope Tumor antigen Type of ca Cancer testis MAGE-1 Melanoma, antigens MAGE-2 Brcast, Head/neck MAGE-3 Bladder, gastric, lung MAGE-12 BAGE GAGE NY-ESO-1 Differentiation Tyrosinase Melanoma antigens TRP-1 TRP-2 gp100 MART-1 MCIR Tumour-specific Ig Idiotype B-ceII NHL, MM antigens CDK4 Melanoma Caspase-B Head/neck -catenin Melanoma CLA Bladder BCR/ABL CML Mutated p21/ras Pancreatic, colon, lung Mutated p53 Colorectal, lung, bladder, head/neck Overexpressed Proteinase 3 CML self antigens WT1 CML, ALL, AML MUC-1 Breast adenocarcinoma Nonmal p53 Breast, colon, other cancers Her2/neu Breast, ovary, hung PAP Prostate PSA Prostate PSMA Prostate G250 Renal cell carcinoma Viral antigens HPV E6/E7 Cervical and penile cancer EBV LMP2a EBV+Hodgkin s discase HCV Liver cancer HHV-8 Kaposi sarcoma Onco foetal CEA Colon, breast, antigens pancreatic cancer -Fetoprotein Liver Cancer 5T4 Many Carcinomas Onco-trophoblast (Including colon, glycoprotein gastric, breast, cervix, ovary, lung, renal cell) NHL: non-hodgkin lymphoma, MM: multiple myeloma, CML: chronic myeloid leukaemia, ALL: acute lymphoblastic leukaemia, AML: acute myeloid leukaemia, CEA: carcinoembryonic antigen, HPV: human papilloma virus, EBV: Epstein-Barr virus, HCV: hepatitis C virus, HHv: human herpes virus. proportion of antigen-positive tumour types is very variable.

5 Cancer Vaccines 59 Table III. The type of cancer vaccines and manufacturing techniques Type Manufacturing techniques (whole cell) Emulsion CTL epitope Liposome CTL epitope Lipopeptide CTL epitope +cytokine adenovirus vaccinia virus, Cytokine B7 gene cytokine gene DNA plasmid

6 60 Eun-Wha Son, et al.

7 Cancer Vaccines 61 Table IV. The current development of cancer vaccines using dendritic cells Materials Company Property Dendreon ( ), APC8020 ( ). 1 ( 02)., APC8015 ( 02) Provenge Dendreon ( ). 3 ( 02) Mylovenge. 2 ( 02) APC8024,,. 1 ( 02) Ex vivo Geron ( ). / Genzyme Molecular Melan-A/Mart-1 gp100 Oncology ( ), ex vivo Massachusetts ( ). 1/2 ( 02) Genzyme Molecular Oncology ( ), Beth Israel 1/2 Deaconess ( ), Dana-Farber ( ) Aastrom Biosciences ( ), Stanford ( ), DC-I Aastrom Biosciences ( ), ex vivo DC-I Zellera DCVax-Prostate Northwest Biotherapeutics ( ). 1/2 DCVax-Brain. 2. IL13 Sanofi-Synthelabo ( ),. 2 ( 02) (IDD3) Immuno-Designed. Sanofi Molecules ( ) IDM 20. ( ) CpG Coley Pharmaceutical ( ) CpG.

8 62 Eun-Wha Son, et al. TK gene Vaccinia Promoter TK gene Vaccinia Promoter Restriction-enzyme cleavage site Plasmid Recombinant plasmid TK gene Cleavage and ligation Gene from tumor cell Transfection TK gene Tissue-culture cells Homologous recombination BUdr selection Recombinant vaccinia Vactor vaccine DNA encoding Ag from tumor cell Vaccine virus Infection Figure 2. The generation of recombinant viral cancer vaccines.

9 Cancer Vaccines 63 Monitor Immune & Clincal response Immuunogenicity by ELISPOT, ELISA & Proliferation Lymphoma Cellulant Lymph node biopsy DNA Ig Idiotype Vaccine Protein Ig Idiotype Vaccine Vaccinte patients Infection defective adeonvirus with CD40L/ IL-2 Activate on CD40L fibroblast (in vitro expansion of lymphpma cells) Irradiate& preserve Clone idiotype cdna from lymphoma cells Assemble as a scfγ Express in plasmid vector with T helper epitope Make hybridoma with B lymphoma Produce idiotypic immunoglobulin Formulate with adjuvant and helper protein (KLH) Limited Cell Vaccine Unlimited DNA vaccine Unlimited Protein vaccine TIM IL-10 Mature DC HLA Class I & II B7.1 B7.2 Effector HTL Naive HTL CD28 CTLA-4 Naïve CTL Th1 TCR CD4 CD40-L IL-13 TGFβ IL-10 Th2 TCR CD4 CD25 NKT cell Tr cell B cell ROS CD40 CD11b Gr-1 Myeloid suppressor cell Antibodies (IgM, IgG) TAA HSP dsdna TCR CD8 NK cell Perforin Granzyme FAS-L FAS Perforin Granzyme FAS-L Effector CTL B7-H1 Tolerogenic DC FAS-L Class I HLA & TAA-derived peptide Tumor cells PGE2 TGFβ NO Complement-dependent cytotoxicity(cdc) & antibody-dependent cellular cytotoxicity(adcc) Figure 3. The strategy of anti-idiotype vaccine generation to treat lymphoma.

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12 66 Eun-Wha Son, et al. G, Morrison SL, Penichet ML. Protein vaccination with the HER2/neu extracellular domain plus anti-her2/neu antibody-cytokine fusion proteins induces a protective anti- HER2/neu immune response in mice. Vaccine 21; , Blumberg BS, Larouze B, London WT, Werner B, Hesser JE, Millman I, Saimot G, Payet M: The relation of infection with the hepatitis B agent to primary hepatic carcinoma. Am J Pathol 81; , Davidson EJ, Faulkner RL, Sehr P, Pawlita M, Smyth LJ, Burt DJ, Tomlinson AE, Hickling J, Kitchener HC, Stern PL: Effect of TA-CIN (HPV 16 L2E6E7) booster immunisation in vulval intraepithelial neoplasia patients previously vaccinated with TA-HPV (vaccinia virus encoding HPV 16/18 E6E7). Vaccine 22; , Humphrey LJ, Boehm B, Jewell WR, Boehm OR: Immunologic response of cancer patients modified by immunization with tumor vaccine. Ann Surg 176; , Antonia S, Mule JJ, Weber JS: Current developments of immunotherapy in the clinic. 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<31342E20BECFB9E9BDC5C0C720B0B3B9DFB5BFC7E22E687770> R&D 동향분석보고서 암백신의 개발 동향 손은수 Ⅰ. 서론 1 Ⅱ. 기술개발동향 1 1. 기술의 개요 및 특성 1 2. 연구개발동향 3 1) 해외동향 5 2) 국내동향 8 Ⅲ. 기술특성분석 9 1. 암백신의 개발특성 9 2. 암백신의 개발 전략 10 1) T세포에 의해 인식되는 specific 암항원 13 2) Shared 암특이 항원 13 3)